Oxidative fluorination of aromatic derivatives by copper (II) fluoride and silver (I) fluoride

ABSTRACT

The subject invention provides methods of fluorinating an aromatic or chloroaromatic compound comprising combining an aromatic compound, a chloroaromatic compound, a mixture of aromatic compounds, a mixture of chloroaromatic compounds, or a mixture of chloroaromatic and aromatic compounds and a fluorinating composition comprising at least one active fluorinating agent selected from the group consisting of CuF 2 , AgF, HgF 2 , TeF 4 , MnF 4 , FeF 3 , and CoF 2-4  and at least one support selected from the group consisting of activated carbon, ZnF 2 , CaF 2 , MgF 2 , AIF 3 , and combinations of activated carbon, ZnF 2 , CaF 2 , MgF 2 , or AlF 3 .

BACKGROUND

Fluorobenzene, a chemical used to control carbon content in steel manufacturing or an intermediate for pharmaceuticals, pesticides and other organic compounds, is typically produced by the reaction of aniline and sodium nitrite in the presence of hydrogen fluoride.

U.S. Pat. Nos. 6,087,543 and 6,166,273 provide improved methods for the fluorination of aromatic ring compounds or benzene. However, these patents provide relatively low yields of desired compounds. Accordingly, there is still a need for efficient commercial processes for preparing fluorobenzene or, more generally, fluorinating compounds having a benzene nucleus using less expensive materials.

SUMMARY OF THE INVENTION

The subject invention provides methods of fluorinating an aromatic or chloroaromatic compound comprising combining an aromatic compound, a chloroaromatic compound, a mixture of aromatic compounds, a mixture of chloroaromatic compounds, or a mixture of chloroaromatic and aromatic compounds and a fluorinating composition comprising at least one active fluorinating agent selected from the group consisting of CuF₂, AgF, HgF₂, TeF₄, MnF₄, FeF₃, and CoF₂₋₄ and at least one support selected from the group consisting of activated carbon, ZnF₂, CaF₂, MgF₂, AlF₃, and combinations of activated carbon, ZnF₂, CaF₂, MgF₂, or AlF₃. Aromatic and chloroaromatic compounds that are to be fluorinated can be substituted with a variety of inert substituents. In certain embodiments, the compounds are substituted with 1, 2, or 3 inert substituents. We have, unexpectedly, found that contacting aromatic or chloroaromatic compounds with a mixture of metal fluorides results in an increased yield of fluorinated compounds.

DETAILED DESCRIPTION

In a first embodiment, the subject invention provides a method of fluorinating an aromatic or chloroaromatic compound comprising combining an aromatic compound, a chloroaromatic compound, a mixture of aromatic compounds, a mixture of chloroaromatic compounds, or a mixture of chloroaromatic and aromatic compounds and a fluorinating composition comprising at least one active fluorinating agent selected from the group consisting of CuF₂, AgF, HgF₂, TeF₄, MnF₄, FeF₃, and CoF₂₋₄ and at least one support selected from the group consisting of activated carbon, ZnF₂, CaF₂, MgF₂, AlF₃, and combinations of activated carbon, ZnF₂, CaF₂, MgF₂, or AlF₃ and heating the combined components to a temperature of at least 350° C. Optionally, fluorinated aromatic or chloroaromatic compounds are then recovered from the reaction mixture.

A second embodiment of the subject invention provides methods of fluorinating an aromatic compound comprising the steps of:

a) mixing at least one active fluorinating agent selected from the group consisting of CuF₂, AgF, HgF₂, TeF₄, MnF₄, FeF₃, and CoF₂₋₄ with at least one support selected from the group consisting of activated carbon, ZnF₂, CaF₂, MgF₂, AlF₃, and combinations of activated carbon, ZnF₂, CaF₂, MgF₂, or AlF₃;

b) heating said mixture to a temperature of at least 350° C.; and

c) contacting said mixture with an aromatic compound, a chloroaromatic compound, a mixture of aromatic compounds, a mixture of chloroaromatic compounds, or a mixture of chloroaromatic and aromatic compounds and, optionally, recovering fluorinated aromatic or chloroaromatic compounds.

In either of the foregoing embodiments, the mixture of compounds can be heated to temperatures of at least 400° C., at least 425° C., at least 450° C., or at least 500° C. Aromatic or chloroaromatic compounds for use in either method can be one compound, or any combination of compounds, selected from the group consisting of benzene, chlorobenzene, substituted benzene, substituted chlorobenzene, pyridines, chloropyridines, substituted pyridines, substituted chloropyridines, naphthalene, substituted naphthalenes, chloronapthalene, substituted chloronaphthalenes, toluene, chlorotoluene, substituted toluene, and substituted chlorotoluene. As indicated supra, aromatic and chloroaromatic compounds can be substituted with any number of inert substituents. In certain embodiments, the compounds are substituted with 1, 2, or 3 inert substituents.

The methods of the subject invention utilize fluorinating compositions that comprise at least one active fluorinating agent selected from the group consisting of CuF₂, AgF, HgF₂, TeF₄, MnF₄, FeF₃, and CoF₂₋₄ and at least one support selected from the group consisting of activated carbon, ZnF₂, CaF₂, MgF₂, AlF₃, and combinations of activated carbon, ZnF₂, CaF₂, MgF₂, or AlF₃. In certain embodiments of the subject invention, the fluorinating composition comprises CuF₂ and AgF in various ratios. These ratios can be manipulated such that the fluorinating composition is pure CuF₂ or pure AgF. Alternatively, the fluorinating compositions can comprise various ratios of CuF₂ and AgF. In various embodiments of the subject invention, fluorinating compositions containing AgF is used to fluorinate chloroaromatic compounds. In other embodiments of the invention, fluorinating compositions comprising CuF₂ is used to fluorinate aromatic hydrocarbons.

A process is also provided for increasing the fluorine content of an aromatic ring compound or a chloroaromatic ring compound (e.g., a benzene ring, a pyridine ring, a benzene ring substituted with from 1 to 3 inert substituents and a pyridine ring substituted with from 1 to 3 inert substituents). The process comprises (a) contacting the ring compound with a metal fluoride composition comprising CuF₂ and/or AgF and another metal fluoride (a support) at a temperature above 300° C. Such temperatures are sufficient to transfer fluorine atoms to the aromatic ring, thereby chemically reducing the metal fluoride composition; (b) oxidizing the reduced metal fluoride composition from (a) in the presence of HF to regenerate a metal fluoride composition comprising CuF₂ and/or AgF; and (c) employing regenerated metal fluoride composition of (b) in (a).

Oxidative fluorination of aromatic compounds using transition metal fluorides is schematically represented below.

With the simple metal fluorides, the fluorinating power depends on the redox potentials of the metal ions involved. Fluorides of the metal ions with E⁰>1 are very strong fluorinating agents giving rise to saturated products. Fluorides of the metal ions with E⁰<0 are inert towards aromatics. On the other hand, fluorides of the metal ions with 1>E⁰>0 are mild fluorinating agents. Metal fluorides useful as mild fluorinating agents in the present invention include but are not limited to CuF₂, AgF, HgF₂, and Hg₂F₂. As illustrated in the examples attached hereto, a 73% conversion of benzene to fluorobenzene and difluorobenzene (ratio of fluorobenzene to difluorobenzene=88:12) was obtained when benzene was contacted with a mixture of CuF₂ and AlF₃ (CuF₂:AlF₃ ratio=1:2) at a temperature of 500° C. At temperatures of 450° C., 44.3% conversion of benzene to fluorobenzene and difluorobenzene was observed (with a fluorbenzene:diflorobenzene ratio of 91:9). At 400° C., fluorobenzene was formed selectively with a yield of 24%. The use of CaF₂ or MgF₂ provided similar results to the use of AlF₃.

As is also illustrated in the examples, chlorobenzene can be converted to a mixture of fluorobenzene, difluorobenzene, and chlorofluorobenzene when reacted with mixtures of CuF₂ and AlF₃ (ratio of 1:2). At temperatures of 500° C., chlorobenzene is converted to fluorobenzene, difluorobenzene, and chlorofluorobenzene at a ratio of 85:7:9 (with a yield of 65%).

Additionally, we have found that ortho-, meta-, and para-chlorotoluenes can be converted to mixtures of fluorotoluenes when reacted with AgF at temperatures of at least about 350° C. with conversion yields of 29%, 47%, and 57% respectively. Ortho- and meta-dichlorobenzenes are converted to meta-difluorobenzene (12% and 20% conversion respectively) plus chlorofluorobenzene (6.7% and 14.5% respectively). All chlorofluorobenzenes exhibited conversion to one product (meta-fluorobenzene) under the reaction conditions.

Following are examples that illustrate procedures for practicing the invention. These examples should not be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.

EXAMPLE 1 Fluorination of Benzene Utilizing AlF₃ and CuF₂ as the Fluorinating Agent

Anhydrous AlF₃ (ALFAAESAR, 99.5%) and anhydrous CuF₂ (ALFAAESAR, 99.5%) were used. To a weighed amount of CuF₂, AlF₃ (˜35 mesh size) was mixed in different ratios (1:1, 1:1.5, 1:2, 1:2.5, 1:3). In a typical fluorination experiment, the metal fluoride mixture was loaded into a hastelloy reactor tube in a dry box. The reactor tube was heated to 500° C. under a flow of Ar gas. The flow rate of the carrier gas was adjusted to 25 mL/min. Vaporized benzene was passed over the heated fluoride mixture. The duration of the reaction was about 1½ to 2½ hrs. At the end of the reaction, the reactor tube was swept out with the carrier gas. The organic product was analyzed using HP 6890 GC/5973 Mass Spectrometer. The inorganic residue was analyzed by powder X-ray diffractometer (XRD PHILIPS APD 3720).

Percentage conversions of benzene to the fluorinated products, m-fluorobenzene, flurobenzene, and o-fluorobenzene, where the amount of AlF₃ increases and CuF₂ remains constant are given in Table 1. TABLE 1 Products Fluoride Mixture Temperature (° C.)

CuF₂(3.5 g) + AlF₃ 500 — 19.7 0.8 1:1 CuF₂(3.5 g) + AlF₃ 500 — 32.7 0.9 1:1.5 CuF₂(3.5 g) + AlF₃ 500 2.4 48.1 1.6 1:2 CuF₂(3.5 g) + AlF₃ 500 — 40.1 1.0 1:2.5 CuF₂(3.5 g) + AlF₃ 500 — 28.6 1.0 1:3

On the basis of the above results, the ratio of CuF₂ to AlF₃ was fixed as 1:2, and additional experiments were carried out at 450° C. and 425° C. The results are given in Table 2. TABLE 2 Products and Product Yields Fluoride Mixture Temperature (° C.)

CuF₂(5.0 g) + AlF₃ 1:2 500 5.4 63.1 3.4 CuF₂(5.0 g) + AlF₃ 1:2 450 2.4 40.5 1.4 CuF₂(5.0 g) + AlF₃ 1:2 425 — 23.8 — From the powder X-ray analysis of the inorganic residue, reduction of CuF₂ to metallic copper was observed.

Introducing the benzene in fractions tested the consistency of reactivity of the fluoride bed. The results are given in Table 3. TABLE 3 Products Fluoride mixture Benzene (ml) Temperature (° C.)

CuF₂(5.0 g) + 0.5 500 7.2 65.8 3.8 AlF₃ 1:2 0.5 500 5.0 63.0 3.4 0.5 500 2.9 52.6 2.5 0.5 500 — 34.9 1.2 CuF₂(5.0 g) + 0.5 425 — 27.9 — AlF₃ 1:2 0.5 425 — 22.0 — 0.5 425 — 19.9 — 0.5 425 — 17.0 —

EXAMPLE 2 Fluorination of Benzene Utilizing AlF₃ and MF₂ (M═Ca, Zn, Mg) as the Fluorinating Agent

Additional fluorination experiments using other materials such as CaF₂, ZnF₂, MgF₂ and activated carbon as additives were carried out. When benzene was treated with the activated carbon added copper fluoride, no fluorination was observed. The experimental conditions as mentioned in Example 1 were followed and the results are presented in Table 4. TABLE 4 Products Additives Tem- perature (° C.)

CaF₂ 500 6.1 51.2 3.1 MgF₂ 500 4.6 44.0 2.6 ZnF₂ 500 — 38.2 1.7

EXAMPLE 3 Fluorination of Chlorobenzene

Fluorination of monochlorobenzene was carried out using CuF₂. Percentage conversion to fluorinated derivatives was improved by adding AlF₃ to CuF₂. The experimental conditions as mentioned in Example 1 were followed. Percentage conversions of chlorobenzene to the fluorinated products for differing CuF₂ and AlF₃ ratios are given in Table 5. TABLE 5 Products Fluoride Mixture Temperature ° C.

CuF₂(5.0 g) 500 2.2 7.4 29.9 0.7 2.9 4.1 CuF₂(3.5 g) + 500 3.8 9.7 35.0 0.8 2.8 3.4 AlF₃ 1:1 CuF₂(3.5 g) + 500 2.7 9.6 40.5 0.7 2.3 3.7 AlF₃ 1:1.5 CuF₂(3.5 g) + 500 4.1 12.2 55.2 0.9 2.4 3.4 AlF₃ 1:2 CuF₂(3.5 g) + 500 4.3 13.3 51.7 1.0 3.4 4.0 AlF₃ 1:2.5 CuF₂(3.5 g) + 500 3.2 9.9 48.3 0.8 3.1 4.3 AlF₃ 1:3

On the basis of the above results the ratio of CuF₂ to AlF₃ was fixed as 1:2, and additional experiments were carried out at 450° C., 425° C. and 400° C. The results are given in Table 6. TABLE 6 Products and Product Yields Fluoride Mixture Temperature ° C.

CuF₂(5.0 g) + 500 8.3 8.8 65.7 1.8 3.6 3.2 AlF₃ 1:2 CuF₂(5.0 g) + 450 3.7 13.6 56.6 — 2.8 3.4 AlF₃ 1:2 CuF₂(5.0 g) + 425 0.9 11.3 30.3 — 0.9 — AlF₃ 1:2 CuF₂(5.0 g) + 400 — 4.1 18.0 — — — AlF₃ 1:2

Reduction of copper fluoride to metallic copper and the formation of CuCl were observed from the powder X-ray analysis of the inorganic residue.

EXAMPLE 4 Fluorination of Monofluorobenzene

The experimental conditions as mentioned in Example 1 were followed. The percentage conversions of monofluorobenzene to difluoro derivatives are given in Table 7. Powder X-ray diffraction analysis indicated the reduction of copper fluoride to metallic copper on reaction with monofluorobenzene. TABLE 7 Products and Product Yields Fluoride Mixture Temperature ° C.

CuF₂(3.5 g) 500 2.0 1.2 CuF₂(5.0 g) 500 6.9 2.8 CuF₂(5.0 g) + 500 21.2 7.0 AlF₃ 1:2

EXAMPLE 5 Fluorination of Chloroaromatics Using AgF as the Fluorinating Agent

Fluorination of Chlorotoluenes

Experiments attempting to fluorinate chloroaromatics using AgF were carried out in exactly the same manner as those carried out with CuF₂ in Example 1. The product yields of a constant temperature fluorination of all the chlorotoluenes utilizing AgF as the fluorinating agent is shown in Table 8. TABLE 8 Product Yield % Reactants Temp. ° C.

350 13.9 14.4 0.5 3.3

350 6.7 25.7 15 7.7

350 0.6 35.8 20.8 3.9

Attempts to flourinate the resulting fluoroaromatic products listed in Table 1 yielded only a small increase in total fluoronation. The increased fluorination is shown in Table 9 for flourobenzene and flurotoluene. TABLE 9 Reactants Temperature ° C. Product Yields

350 Only 2-4% fluorination

350 Fluorination of Dichlorobenzenes

All three dichlorobenzenes were fluorinated using the methods disclosed in Example 1. The fluorinating agent utilized was AgF and the four resulting product yields are shown in Table 10. TABLE 10 Product Yields % Reactants Temp. ° C.

350 12.2 2.5 4.2 —

350 20.4 3.8 5.7 5.0

350 1.4 — 3.4 4.2 Fluorination of Chlorofluorobenzenes

Fluorination of the three chlorofluorobenzenes as shown in the product yields in Table 11 selectively result in conversion to meta-fluorobenzene. The product yields of this fluorination reaction are shown in Table 11. TABLE 11 Products and Reactants Temperature ° C. Product Yields %

350 20.3

350 39.6

350  5.9 Fluorination of 2-Chloropyridine

Fluoroaromatics other than fluorobenzenes can also be fluorinated utilizing the process of the present invention. As the following schematic shows, a pyridine can be fluorinated with AgF to yield a fluorinated pyridine. 

1. A method of fluorinating an aromatic compound or chloroaromatic compound comprising the steps of: a) mixing at least one active fluorinating agent selected from the group consisting of CuF₂, AgF, HgF₂, TeF₄, MnF₄, FeF₃, and CoF₂₋₄ with at least one support selected from the group consisting of activated carbon, ZnF₂, CaF₂, MgF₂, AlF₃, and combinations of activated carbon, ZnF₂, CaF₂, MgF₂, or AlF₃; b) heating said mixture to a temperature of at least 300° C. or 350° C.; and c) contacting said mixture with an aromatic compound, a chloroaromatic compound, a mixture of aromatic compounds, a mixture of chloroaromatic compounds, or a mixture of chloroaromatic and aromatic compounds.
 2. The method according to claim 1, wherein said method further comprises recovering fluorinated aromatic or chloroaromatic compounds.
 3. The method according to claim 1, wherein said temperature is at least 400° C.
 4. The method according to claim 1, wherein said temperature is at least 425° C.
 5. The method according to claim 1, wherein said temperature is at least 450° C.
 6. The method according to claim 1, wherein said temperature is at least 500° C.
 7. The method according to claim 1, wherein said aromatic or chloroaromatic compound is selected from the group consisting of benzene, chlorobenzene, substituted benzene, substituted chlorobenzene, pyridines, chloropyridines, substituted pyridines, substituted chloropyridines, naphthalene, substituted naphthalenes, chloronaphthalene, substituted chloronaphthalenes, toluene, chlorotoluene, substituted toluene, and substituted chlorotoluene.
 8. The method according to claim 1, wherein aromatic compounds are contacted with said mixture.
 9. The method according to claim 1, wherein chloroaromatic compounds are contacted with said mixture.
 10. The method according to claim 1, wherein a mixture of chloroaromatic and aromatic compounds are contacted with said mixture.
 11. The method according to claim 9, wherein said mixture comprises AgF and at least one support.
 12. The method according to claim 8, wherein said aromatic compounds are aromatic hydrocarbons.
 13. The method according to claim 12, wherein said aromatic compounds are contacted with a mixture comprising CuF₂ and at least one support.
 14. The method according to claim 9, wherein said choloroaromatic compound is ortho-dichlorobenzene, para-dichlorobenzene, meta-dichlorobenzene, a chloropyridine, chloronapthalene, a chlorpyridine, chlorotoluene, substituted ortho-dichlorobenzene, substituted para-dichlorobenzene, substituted meta-dichlorobenzene, a substituted chloropyridine, substituted chloronapthalene, a substituted chlorpyridine, substituted chlorotoluene, or mixtures thereof.
 15. The method according to claim 14, wherein said mixture is contacted by a mixture comprising AgF and at least one support.
 16. The method according to claim 15, wherein said mixture consists of AgF and at least one support.
 17. The method according to claim 12, wherein said aromatic compounds are contacted with a mixture consisting of CuF₂ and at least one support.
 18. The method according to claim 11, wherein said mixture further comprises CuF₂.
 19. The method according to claim 13, wherein said mixture further comprises AgF.
 20. A method of fluorinating an aromatic compound comprising combining an aromatic compound, a chloroaromatic compound, a mixture of aromatic compounds, a mixture of chloroaromatic compounds, or a mixture of chloroaromatic and aromatic compounds and a fluorinating composition comprising at least one active fluorinating agent selected from the group consisting of CuF₂, AgF, HgF₂, TeF₄, MnF₄, FeF₃, and CoF₂₋₄ and at least one support selected from the group consisting of activated carbon, ZnF₂, CaF₂, MgF₂, AlF₃, and combinations of activated carbon, ZnF₂, CaF₂, MgF₂, or AlF₃ and heating the combined components to a temperature of at least 350° C. 